Pyrroloazepine compounds

ABSTRACT

Disclosed are pyrroloazepine compounds and their salts. These pyrroloazepine compounds are represented by the following formula:                    
     wherein the dashed line indicates the presence or absence of a bond; and, when the bond is present, Z 2  is not present and Z 1  is H but, when the bond is absent, Z 1  and Z 2  are both Hs; Z 1  is H and Z 2  is OH; Z 1  and Z 2  are both SR 5 s in which R 5  is alkyl, aralkyl or aryl; or Z 1  and Z 2  are combined together to represent O, NOR 6  in which R 6  is H, alkyl, aralkyl or aryl, or C 2 -C 3  alkylenedithio; R is H, alkyl, cycloalkyl, cycloalkyl-alkyl or aralkyl; and the ring P is a specific pyrrole ring. These pyrroloazepine compounds and salts are effective as preventives or therapeutics for general circulatory diseases such as hypertension, heart failure, ischemic hear diseases, cerebrovascular disturbances and peripheral circulatory disturbances. Their production processes are also disclosed.

This application is a Divisional of U.S. Application Ser. No.09/147,248, filed on Nov. 12, 1998 now allowed, which was filed asInternational Application No. PCT/JP98/01085 filed Mar. 16, 1998.

TECHNICAL FIELD

This invention relates to novel pyrroloazepine compounds. Morespecifically, this invention is concerned with pyrrolo[3,2-c]azepinecompounds, pyrrolo[3,4-c]azepine compounds and salts thereof, saidcompounds and salts having strong α₁-blocking action and serotonin-2receptor antagonistic action and being useful as pharmaceuticals for usein the prevention or treatment of circulatory diseases such ashypertension, heart failure, ischemic heart diseases such as anginapectoris, myocardial infarction and post-PTCA restenosis,cerebrovascular disturbances such as cerebral infarction and cerebralsequelae after subarachnoid hemorrhage, and peripheral circulatorydisturbances such as arteriosclerosis obliterans, thromboangiitisobliterans, Raynaud disease and Buerger disease; their preparationprocess; and pharmaceuticals containing them as effective ingredients.

BACKGROUND ART

As pharmaceuticals which act on the circulatory system, many productsare known to date, including a variety of products developed asvasodilators.

Among such vasodilators, α₁-blockers led by prazosin are the targets ofactive developments, because they have advantages such that (1) theirantihypertensive action is strong and reliable, (2) they do notadversely affect lipometabolism or saccharometabolism and (3) they canbe used easily for hypertensives suffering from complication. Asα₁-blockers which are currently in clinical use, bunazosin, terazosin,urapidil, doxazosin and the like can be mentioned in addition toprazosin. Further, medicines having α₁-blocking action andanti-serotonin action in combination are expected to become still bettertherapeutics for hypertension, because they have possibility to reduceside effects, such as orthostatic hypotension and reflex tachycardia,induced by antihypertensive action which is based on α₁-blocking action.

Further, a hypertensive is considered to be prone to an ischemic heartdisease or peripheral circulatory disturbance, since his or her plateletaggregating ability has been generally potentiated to have higherthrombophilia. As one of those taking part in thrombosis, serotonin isknown. Serotonin is a compound contained abundantly in platelets, whichare a blood component, and in a central nervous system, on the otherhand, it acts as a neurotransmitter. In platelets, it is released uponstimulation by thromboxane A₂, ADP, collagen or the like, andsynergistically acts on release of various platelet aggregation factorsthrough activation of serotonin-2 receptors in the platelets andvascular smooth muscle cells and also on vasoconstriction bynorepinephrine through α₁ receptors, thereby inducing strong plateletaggregation and vasoconstriction [P.M. Vanhoutte, “Journal ofCardiovascular Pharmacology”, Vol. 17 (Suppl. 5), S6-S12 (1991)].

Serotonin is also known to potentiate proliferation of vascular smoothmuscle cells [S. Araki et al., “Atherosclerosis”, Vol. 83,pp.29-34(1990)]. It has been considered that, particularly whenendothelial cells are injured as in arteriosclerosis or myocardialinfarction, the vasoconstricting action and thrombus forming action ofserotonin are exasperated, thereby reducing or even stopping bloodsupply to myocardial, cerebral and peripheral organs [P. Golino et al.,“The New England Journal of Medicine”, Vol. 324, No. 10,pp.641-648(1991), Y. Takiguchi et al., “Thrombosis and Haemostasis”,Vol. 68(4), pp.460-463(1992), A. S. Weyrich et al., “American Journal ofPhysiology”, Vol. 263, H349-H358(1992)]. Being attracted by such actionsof serotonin or serotonin-2 receptors, various attempts are now underway to use a serotonin-2 receptor antagonist as a pharmaceutical forischemic diseases of the heart, the brain and peripheral tissues.

From the foregoing, a medicine having α₁-blocking action and serotonin-2receptor antagonistic action in combination is expected to havevasodilative action, antiplatelet action and vascular smooth muscleproliferation inhibiting action, and is considered to become a medicineextremely effective for the prevention or treatment of not onlyhypertension but also general circulatory diseases such as heartfailure, ischemic heart diseases such as angina pectoris, myocardialinfarction and post-PTCA restenosis, cerebrovascular disturbances suchas cerebral infarction and cerebral sequelae after subarachnoidhemorrhage, and peripheral circulatory disturbances such asarteriosclerosis obliterans, thromboangiitis obliterans, Raynaud diseaseand Buerger disease.

Until today, several medicines have been reported to have α₁-blockingaction and serotonin-2 receptor antagonistic action in combination. Theyare however still accompanied with many problems to be improved inpotency, selectivity to other receptors, toxicity, side effects and thelike. There is hence an outstanding desire for the provision of a stillbetter compound.

DISCLOSURE OF THE INVENTION

In view of the foregoing circumstances, the present inventors haveproceeded with extensive research, resulting in the finding ofpyrrolo[3,2-c]azepine compounds and pyrrolo[3,4-c]azepine compoundswhich have strong α₁-blocking action and serotonin-2 receptorantagonistic action in combination, have low toxicity and less sideeffects, and are useful for the prevention and treatment of generalcirculatory diseases such as hypertension, heart failure, ischemic heartdiseases, cerebrovascular disturbances and peripheral circulatorydisturbances.

The present invention has been completed based on the above describedfindings. A first object of the present invention is to provide apyrroloazepine compound or a salt thereof, said pyrroloazepine compoundbeing represented by the following formula (I):

wherein the ring P represented by

means a pyrrole ring represented by the following structure:

in which A represents an alkylene group, an alkenylene group or analkynylene group, and Y represents a group

in which W represents CH, C═ or a nitrogen atom; and, when W representsCH, m stands for 0 or 1, B represents an oxygen atom, a sulfur atom, acarbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group,an alkenylene group, a group —C(OH)R₁— in which R₁ represents asubstituted or unsubstituted aryl group, a group —CHR₂— in which R₂represents a substituted or unsubstituted aryl group, or a substitutedor unsubstituted, cyclic or acyclic acetal group; when W represents C═,m stands for 1, B represents a group

in which the double bond is coupled with W and R₃ represents asubstituted or unsubstituted aryl group or a substituted orunsubstituted aralkyl group; when W represents a nitrogen atom, m standsfor 0 or 1, and B represents a carbonyl group, a sulfonyl group, analkylene group, an alkenylene group or a group —CHR₄— in which R₄represents a substituted or unsubstituted aryl group; E₁ and E₂ eachindependently represents a hydrogen atom or a lower alkyl group; and Drepresents a substituted or unsubstituted aromatic hydrocarbon group ora substituted or unsubstituted aromatic heterocyclic group;

the dashed line indicates the presence or absence of a bond; and, whenthe bond indicated by the dashed line is present, Z₂ is not present andZ₁ represents a hydrogen atom but, when the bond indicated by the dashedline is absent, Z₁ and Z₂ both represent hydrogen atoms; Z₁ represents ahydrogen atom and Z₂ represents a hydroxyl group; Z₁ and Z₂ bothrepresent groups SR₅ in which R₅ represents a substituted orunsubstituted alkyl group, a substituted or unsubstituted aralkyl groupor a substituted or unsubstituted aryl group; or Z₁ and Z₂ are combinedtogether to represent an oxygen atom, a group NOR₆ in which R₆represents a hydrogen atom, a substituted or unsubstituted alkyl group,a substituted or unsubstituted aralkyl group or a substituted orunsubstituted aryl group, or a group

in which G represents a substituted or unsubstituted ethylene group or asubstituted or unsubstituted trimethylene group; and

R represents a hydrogen atom, a linear or branched alkyl group, acycloalkyl group, a cycloalkyl-alkyl group or a substituted orunsubstituted aralkyl group.

A second object of the present invention is to provide a preparationprocess of the pyrroloazepine compound (I) or its salt.

Further, a third object of the present invention is to provide apharmaceutical which comprises the pyrroloazepine compound (I) or itspharmacologically-acceptable salt as an effective ingredient and isusable for the treatment or the like of circulatory diseases.

BEST MODES FOR CARRYING OUT THE INVENTION

In the pyrroloazepine compound (I) of the present invention, preferredexamples of the group R can include a hydrogen atom; linear or branchedalkyl groups having 1-8 carbon atoms preferably, such as methyl, ethyl,n-propyl, isopropyl and n-pentyl; cycloalkyl groups having 3-8 carbonatoms, such as cyclopropyl, cyclopentyl and cyclohexyl; cycloalkyl-alkylgroups having 4-8 carbon atoms, such as cyclopropylmethyl,cyclohexylmethyl and cyclohexylethyl; and aralkyl groups having 7-22carbon atoms, such as diphenylmethyl, benzyl and phenethyl. One or morehydrogen atoms of each of these groups may be substituted by a likenumber of halogen atoms such as fluorine, chlorine and/or bromine atoms,alkyl groups having 1-4 carbon atoms preferably, such as methyl and/orethyl, and/or alkoxy groups having 1-4 carbon atoms preferably, such asmethoxy and/or ethoxy. Particularly preferred examples of the group Rcan be methyl and ethyl.

Further, preferred examples of the group Z₁ and the group Z₂ in thecompound (I) according to the present invention can include thefollowing combinations: when the bond indicated by the dashed line ispresent, Z₂ is not present and Z₁ represents a hydrogen atom; when thebond indicated by the dashed line is absent, Z₁ and Z₂ are both hydrogenatoms, Z₁ and Z₂ both represent the groups SR₅, Z₁ represents a hydrogenatom and Z₂ represents a hydroxyl group, and Z₁ and Z₂ are combinedtogether to represent an oxygen atom, the group NOR₆ or the group

wherein G has the same meaning as defined above.

Preferred examples of R₆ in the group NOR₆ can include a hydrogen atom;linear or branched alkyl groups having 1-4 carbon atoms preferably, suchas methyl and ethyl; aryl groups having 6-14 carbon atoms, such asphenyl and naphthyl; and aralkyl groups having 7-22 carbon atoms, suchas benzyl and phenethyl. One or more of the hydrogen atoms of each ofthese groups may be substituted by a like number of halogen atoms suchas fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4carbon atoms preferably, such as methyl and/or ethyl, and/or alkoxygroups having 1-4 carbon atoms preferably, such as methoxy and/orethoxy. Of these, hydrogen atom and methyl group are particularlypreferred.

Further, preferred examples of G in the group

can include ethylene and trimethylene. One or more of the hydrogen atomsof each of these groups may be substituted by a like number of halogenatoms such as fluorine, chlorine and/or bromine atoms, alkyl groupshaving 1-4 carbon atoms preferably, such as methyl and/or ethyl, arylgroups having 6-14 carbon atoms, such as phenyl and naphthyl, aralkylgroups having 7-22 carbon atoms, such as benzyl and phenethyl, and/oralkylidene groups having 1-4 carbon atoms preferably, such asmethylidene and/or ethylidene.

Preferred examples of R₅ in the group SR₅ can include linear or branchedalkyl groups having 1-4 carbon atoms preferably, such as methyl andethyl; aryl groups having 6-14 carbon atoms such as phenyl and naphthyl;and aralkyl groups having 7-22 carbon atoms such as benzyl andphenethyl. One or more of the hydrogen atoms of each of these groups maybe substituted by a like number of halogen atoms such as fluorine,chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atomspreferably, such as methyl and/or ethyl, and/or alkoxy groups having 1-4carbon atoms preferably, such as methoxy and/or ethoxy.

In the pyrroloazepine compounds (I) of the present invention, the ring Prepresents any one of the following pyrrole rings:

wherein A and Y have the same meanings as defined above.

Preferred examples of the group A can include linear or branchedalkylene groups having 2-10 carbon atoms, such as ethylene,trimethylene, tetramethylene, pentamethylene and octamethylene; linearor branched alkenylene groups having 4-10 carbon atoms, such as2-butenylene and 3-pentenylene; and linear or branched alkynylene groupshaving 4-10 carbon atoms, such as 2-butynylene and 3-pentynylene. One ormore of the hydrogen atoms of each of these groups may be substituted bya like number of halogen atoms such as fluorine, chlorine and/or bromineatoms. Among the above groups, trimethylene, tetramethylene andpentamethylene are particularly preferred.

In the ring P, Y is a group

wherein B, D, E₁, E₂, W and m have the same meanings as defined above.The group, which is contained in the above group and is represented bythe following formula:

wherein E₁, E₂ and W have the same meanings as defined above, is aheterocyclic group derived from piperidine or piperazine, and two orless of the hydrogen atoms on the ring may be substituted by a likenumber of alkyl groups having 1-4 carbon atoms preferably, such asmethyl and/or ethyl.

When the above group is a heterocyclic group derived from piperidine, mstands for 0 or 1 (with the proviso that m stands for 1 when Yrepresents C═), and B represents an oxygen atom, a sulfur atom, acarbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group(an alkylene group having 1-4 carbon atoms preferably, with a methylenegroup being particularly preferred), an alkenylene group (an alkenylenegroup having 2-5 carbon atoms preferably, with a 2-propenylene groupbeing particularly preferred), a group —C(OH)R₁— in which R₁ representsan aryl group having 6-14 carbon atoms, such as phenyl or naphthyl, andone or more hydrogen atoms may be substituted, a group —CHR₂— in whichR₂ represents an aryl group having 6-14 carbon atoms, such as phenyl ornaphthyl, and one or more hydrogen atoms may be substituted, a group

in which the double bond is coupled with W, R₃ represents an aryl grouphaving 6-14 carbon atoms, such as phenyl or naphthyl, or an aralkylgroup having 7-22 carbon atoms, such as benzyl or phenethyl, and thesegroups may be in substituted forms, or a cyclic or acyclic acetal groupin which one or more of the hydrogen atoms may be substituted.

Examples of the cyclic or acyclic acetal group can include:

In the above-described definition of B, preferred examples of thesubstituents for the groups R₁,R₂ can include alkyl groups having 1-4carbon atoms preferably, such as methyl and ethyl; and aryl groupshaving 6-14 carbon atoms, such as phenyl and naphthyl. These groups maybe substituted by one or more of halogen atoms such as fluorine,chlorine and/or bromine, alkoxy groups having 1-4 carbon atomspreferably, such as methoxy and/or ethoxy, hydroxyl groups, cyanogroups, nitro groups and the like.

Exemplary substituents for R₃ can include one or more of halogen atomssuch as fluorine, chlorine and/or bromine, alkyl groups having 1-4carbon atoms preferably, such as methyl and/or ethyl, alkoxy groupshaving 1-4 carbon atoms preferably, such as methoxy and/or ethoxy, andhydroxyl groups. Illustrative of the substituent for the cyclic oracyclic acetal can be halogen atoms such as fluorine, chlorine andbromine, alkyl groups having 1-4 carbon atoms preferably, such as methyland ethyl, aryl groups having 6-14 carbon atoms, such as phenyl andnaphthyl, aralkyl groups having 7-22 carbon atoms, such as benzyl andphenethyl, and alkylidene groups having 1-4 carbon atoms preferably,such as methylidene and ethylidene.

Among these examples of B, particularly preferred is a carbonyl group.

When the heterocyclic group is a group derived from piperazine, m standsfor 0 or 1 (preferably 0), and B represents a carbonyl group, a sulfonylgroup, an alkylene group (preferably, an alkylene group having 1-4carbon atoms, with a methylene group being particularly preferred), analkenylene group (preferably, an alkenylene group having 3-6 carbonatoms, with a 2-propenylene group being particularly preferred), a group—CHR₄— in which R₄ represents an aryl group having 6-14 carbon atoms,such as phenyl or naphthyl.

The above-described R₄ may be substituted further by one or more ofhalogen atoms such as fluorine, chlorine and/or bromine, alkyl groupshaving 1-4 carbon atoms preferably, such as methyl and/or ethyl, and/oralkoxy groups having 1-4 carbon atoms preferably, such as methoxy and/orethoxy.

Among the above-described examples of B, preferred is a substituted orunsubstituted phenylmethylene group.

Preferred examples of D can include aromatic hydrocarbon groups having6-28 carbon atoms preferably, such as a phenyl group in which one ormore of the hydrogen atoms may be substituted and a naphthyl group inwhich one or more of the hydrogen atoms may be substituted.

Other preferred examples of D can include aromatic heterocyclic groups,preferably those each of which is monocyclic or dicyclic and containsthree or less hetero atoms, such as pyridyl, pyrimidinyl,benzisothiazolyl, benzisoxazolyl, indazolyl and indolyl groups in whichone or more of hydrogen atoms may be substituted. Illustrative of thehetero atoms can be oxygen, sulfur and/or nitrogen atoms.

Examples of the substituents for the above aromatic hydrocarbon group oraromatic heterocyclic group can include halogen atoms such as fluorine,chlorine and bromine; alkyl groups having 1-4 carbon atoms preferably,such as methyl and ethyl; alkoxy groups having 1-4 carbon atomspreferably, such as methoxy and ethoxy; aryl groups having 6-14 carbonatoms, such as phenyl and naphthyl; aralkyl groups having 7-22 carbonatoms, such as benzyl and phenethyl; aralkyloxy groups having 7-22carbon atoms preferably, such as benzyloxy; cyano groups; nitro groups;carboxyl groups; alkoxycarbonyl groups (with an alcohol moiety thereofhaving 1-6 carbon atoms preferably); lower alkylsulfonylamino groups(with an alkyl moiety thereof having 1-4 carbon atoms preferably);carbamoyl groups; and hydroxyl groups.

Among these examples of group D, preferred ones can include phenylgroups which may be unsubstituted or substituted by one or more ofhalogen atoms, alkoxy groups and/or hydroxyl groups; benzisothiazolylgroups which may be unsubstituted or substituted by one or more halogenatoms; benzisoxazolyl groups which may be unsubstituted or substitutedby one or more halogen atoms; and indazolyl groups which may beunsubstituted or substituted by one or more halogen atoms. Particularlypreferred are an unsubstituted phenyl group; and phenyl groupssubstituted by one or more of fluorine atoms, methoxy groups and/orhydroxyl groups.

Many of the compounds (I) according to the present invention haveisomers. It is to be noted that these isomers and mixtures thereof areall embraced by the present invention.

Various processes can be employed for the preparation of thepyrroloazepine compounds (I) according to the present invention. It ishowever preferred to prepare them, for example, by any one of theprocesses to be described as Process 2 onwards while using as startingmaterial pyrroloazepine compounds (II) or (II′) available by Process 1which will be described hereinafter.

Process 1:

The pyrroloazepine compounds (II) and (III) useful as starting materialscan be synthesized, for example, by the following process:

Each compound of the formula (II) or the formula (II′) can be obtainedin accordance with the following reaction scheme, namely, by reacting apyrrole-3-carboxylic acid or a derivative thereof represented by theformula (XV) with a β-aminopropionic acid or a derivative thereofrepresented by the formula (XVI′) or an organic or inorganic saltthereof and, if necessary, conducting deprotection to obtain a compoundrepresented by the formula (XVII′) and then subjecting the thus-obtainedcompound to a ring-closing reaction.

wherein Q represents a hydroxyl group, an alkoxy group or an eliminativegroup easily replaceable by an amino group, and R and R₇ have the samemeanings as defined above.

Examples of the eliminative group, which is easily replaceable with anamino group and is represented by the group Q in the compound (XV), caninclude halogen atoms, an acyloxy group and a p-nitrophenoxy group. Onthe other hand, as the carboxyl-protecting group represented by thegroup R₇ in the compound (XVI′), it is possible to use, in addition tolower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl and t-butyl and aralkyl groups having 7-20 carbon atoms, suchas benzyl and 9-anthrylmethyl, conventional protecting groups such asthose described in T. W. Greene: “Protective Groups in OrganicSynthesis” (John Wiley & Sons, Inc.) and the like.

For the synthesis of the compound (XVII′), it is possible to use any oneof various processes disclosed in “Compendium of Organic SyntheticMethods” (WILEY-INTERSCIENCE; A Division of John Wiley & Sons, Inc.) andthe like.

Illustrative synthesis processes of the compound (XVII′) can include aprocess in which a pyrrole-3-carboxylic acid [the compound (XV) in whichQ═OH] and a β-aminopropionic acid or a derivative thereof represented bythe formula (XVI′) or an organic or inorganic salt thereof are treatedwith an organic compound such as diethyl phosphorocyanidate (DEPC),diphenylphosphoryl azide (DPPA), dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride or2-iodo-1-methylpyridinium iodide or an inorganic compound such assilicon tetrachloride or tin tetrachloride, if necessary, in thepresence of an organic or inorganic base; and a process in which apyrrole-3-carboxylic acid is converted into its acid halide, symmetricacid anhydride, mixed acid anhydride, its active ester such asp-nitrophenyl ester, or the like by a method known per se in the art,and is then reacted with the compound (XVI′), if necessary, in thepresence of an organic or inorganic base.

Each compound (XVII′) thus obtained is subjected to a cyclizationreaction, optionally after removing the protecting group by virtue of asuitable method such as the action of an acid or a base, or catalyticreduction. This cyclization reaction is conducted by treating thecompound (XVII′) together with an organic acid such as methanesulfonicacid, an inorganic acid such as sulfuric acid or polyphosphoric acid ora mixture of such an organic or inorganic acid and phosphorus pentoxideat room temperature to 170° C., preferably at 80-120° C. In this case, asolvent which does not take part in the reaction may be added as needed.

As an alternative, the cyclization reaction can also be practiced by,optionally after addition of a catalyst, treating the compound (XVII′)with oxalyl chloride, thionyl chloride, thionyl bromide, oxalyl bromide,phosgene, phosphorus trichloride, phosphorus tribromide, phosphorylchloride, phosphoryl bromide or the like to convert it into itscorresponding acid halide and then treating the acid halide at −20° C.to reflux temperature in the presence of a Lewis acid such as aluminumchloride, aluminum bromide, boron trifluoride-ether complex or tintetrachloride in a solvent such as dichloromethane, 1,2-dichloroethaneor nitromethane. In the above-described reactions, the compound (II) andthe compound (II′) can be formed at varied ratios by changing thereaction conditions. Process 2:

Among the pyrroloazepine compounds (I), compounds (Ia) and (Ia′) in eachof which Z₁ and Z₂ are combined together to represent an oxygen atom canbe synthesized, for example, by any one of the following processes.

Process (a)

Each compound (Ia) or compound (Ia′) can be obtained in accordance withthe following reaction scheme, namely, by reacting a compoundrepresented by the formula (II) or (II′) with a compound represented bythe formula (III) to convert the compound (II) or (II′) into a compoundrepresented by the formula (IV) or (IV′) and then reacting anitrogen-containing compound represented by the formula (V) or a saltthereof to the compound (IV) or (IV′).

wherein A, R, X, X′ and Y have the same meanings as defined above.

In the above-described reactions, the conversion from the compound (II)or (II′) into the compound (IV) or (IV′) can be effected by treating thecompound (II) or (II′) with an organic or inorganic base and thenreacting the compound (III), or by causing the compound (III) to act onthe compound (II) or (II′) in the presence of such a base.

The groups X and X′ in the compound (III) are eliminative groups.Illustrative can be halogen atoms such as chlorine and bromine,alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxygroups such as p-toluenesulfonyloxy.

Exemplary organic or inorganic bases can include sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, sodiumhydride, triethylamine, sodium ethoxide, and potassium t-butoxide.Further, illustrative solvents usable in the above reaction can includeacetone, 2-butanone, acetonitrile, dimethyl sulfoxide, dioxane andtoluene. The reaction can be conducted at −20° C. to reflux temperature.

To prepare the compound (Ia) or (Ia′) from the thus-obtained compound(IV) or (IV′), it is only necessary to react the compound (IV) or (IV′)with the nitrogen-containing compound (V) or an organic acid salt orinorganic acid salt thereof in a solventless manner or in a solvent suchas the above-described solvent, methanol or ethanol at room temperatureto 150° C. In this reaction, an organic base such as triethyl amine,pyridine, collidine or potassium t-butoxide or an inorganic base such aspotassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodiumhydroxide or potassium hydroxide can be used as needed. Further, analkali iodide such as potassium iodide or sodium iodide can also beadded as needed.

Examples of the nitrogen-containing compound (V) can include1-phenylpiperazine, 1-(2-fluorophenyl)piperazine,1-(3-fluorophenyl)piperazine, 1-(4-fluorophenyl)piperazine,1-(4-hydroxyphenyl)piperazine, 1-(2-chlorophenyl)piperazine,1-(3-chlorophenyl)piperazine, 1-(4-chlorophenyl)piperazine,1-(2-methoxyphenyl)piperazine, 1-(3-methoxyphenyl)piperazine,1-(4-methoxyphenyl)piperazine,1-(4-methanesulfonamido-phenyl)piperazine, 1-(4-cyanophenyl)piperazine,1-(4-carbamoylphenyl)piperazine, 1-(4-methoxycarbonyl-phenyl)piperazine,1-(2-pyridyl)piperazine, 1-(2-pyrimidinyl)piperazine,1-benzylpiperazine, 1-diphenyl-methylpiperazine, 1-cinnamylpiperazine,1-benzoyl-piperazine, 1-(4-benzyloxybenzoyl)piperazine,1-(4-hydroxybenzoyl)piperazine, 1-(2-furoyl)piperazine,1-(1,2-benzisoxazol-3-yl)piperazine,1-(1,2-benzisothiazol-3-yl)piperazine, 4-phenylpiperidine,4-benzylpiperidine, α,α-bis(4-fluorophenyl)-4-piperidine-methanol,4-(4-fluorobenzoyl)piperidine, 4-benzoyl-piperidine,4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine,3-(4-fluorobenzoyl)piperidine,4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine,4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidine,4-(6-fluoro-1H-indazol-3-yl)piperidine, 4-(4-fluorophenoxy)piperidine,4-[(4-fluorophenyl)thio]-piperidine,4-[(4-fluorophenyl)sulfinyl]piperidine,4-[(4-fluorophenyl)sulfonyl]piperidine,4-[bis(4-fluorophenyl)methylene]piperidine, and4-(4-fluorobenzoyl)piperidine ethylene acetal. They are either known orcan be readily prepared by known processes or processes similar to suchknown processes.

Process (b)

Further, the compound (Ia) or (Ia′) can be obtained by causing acompound represented by the formula (VI) to act on the compoundrepresented by the formula (II) or (III) in accordance with thefollowing reaction formula:

wherein A, R, X and Y have the same meanings as defined above.

The conversion from the compound (II) or (II′) into the compound (Ia) or(Ia′) is conducted by causing the compound (VI) to act either aftertreatment of the compound (II) or (II′) with an inorganic base or anorganic base or in the presence of an inorganic base or an organic base.Reaction conditions are similar to those employed upon conversion fromthe compound (II) into the compound (IV) and described above underProcess (a) of Process 2. Further, the compound (VI) can be synthesizedby reacting the compound (III) with the compound (V) in a manner knownper se in the art.

Process 3:

Among the pyrroloazepine compounds (I), the compounds (Ic), (Ic′), (If)and (If′) in each of which Z₁ and Z₂ both represent groups SR₅ (in whichR₅ has the same meaning as described above) or Z₁ and Z₂ are combinedtogether to represent the group

wherein G has the same meaning as defined above can be synthesized byany one of the following processes.

Process (a)

The compound (If) or (If′) is obtained in accordance with the followingreaction scheme, namely, by reacting a thiol compound, which isrepresented by the formula (VIIa) or (VIIb) [the compound (VIIa) and thecompound (VIIb) may hereinafter be collectively called “the thiolcompound (VII)”], with a compound (II) or (II′) and then causing acompound (VI) to act.

wherein A, G, R, R₅, X, Y, Z₁′ and Z₂′ have the same meanings as definedabove.

For the conversion from the compound (II) or (II′) into the compound(IX) or (IX′) , a suitable method can be selected from those disclosed,for example, in T. W. Greene: “Protective Groups in Organic Synthesis”(John Wiley & Sons, Inc.) and the like. Describing one example, there isa process in which the thiol compound (VII) and boron trifluoride-ethercomplex are caused to act on the compound (II) or (II′) in chloroform.Further, the conversion from the compound (IX) or (IX′) into thecompound (If) or (If′) can be effected under the same conditions as inthe conversion from the compound (II) into the compound (Ia) describedabove under Process (b) of Process 2.

Process (b)

Each compound represented by the formula (Ic) or (Ic′) can be obtainedby causing the thiol compound (VII) to act on a compound (Ib) or (Ib′)in accordance with the following reaction scheme.

wherein A, G, R, R₅, Y′ Z₁′ and Z₂′ have the same meanings as describedabove.

The conversion from the compound (Ib) or (Ib′) into the compound (Ic) or(Ic′) can be effected under similar conditions as in the conversion offrom the compound (II) into the compound (IX) described above underProcess (a) of Process 3.

Process 4:

Among the pyrroloazepine compounds (I), the compounds (Id) and (Id′) andthe compounds (Ig) and (Ig′) in each of which Z₁ and Z₂ are combinedtogether to represent a group NOR₆ can each be synthesized by any one ofthe following processes.

Process (a)

Each compound (Ig) or (Ig′) is obtained in accordance with the followingreaction scheme, namely, by causing hydroxylamine or a derivativethereof (VIII) or a salt thereof to act on a compound represented by theformula (IV) or (IV′) and then causing a nitrogen-containing compound(V) to act.

wherein A, R, R₆, X and Y have the same meanings as defined above.

The reaction between the compound (IV) or (IV′) and the hydroxylamine orits derivative (VIII) is effected, if necessary, in the presence of anorganic base such as pyridine, triethylamine, collidine or sodiumacetate or an inorganic base such as potassium carbonate or sodiumhydroxide. The hydroxylamine or its derivative (VIII) may also be usedin the form of an organic acid salt or an inorganic acid salt.

The reaction is conducted at 0° C. to reflux temperature, preferably0°C.-100° C. by adding a suitable solvent, for example, methanol,ethanol, propanol, tetrahydrofuran, dimethylformamide or dimethylsulfoxide as needed.

Further, the conversion from the thus-obtained compound (X) or (X′) intothe compound (Ig) or (Ig′) can be effected under similar conditions asin the conversion from the compound (IV) into the compound (Ia) shownabove under Process (a) of Process 2.

Process (b)

Each compound (Id) or (Id′) is obtained by causing hydroxylamine or itsderivative (VIII) or a salt thereof to act on a compound (Ib) or (Ib′)in accordance with the following reaction formula.

wherein A, R, R₆ and Y have the same meanings as defined above.

The conversion from the compound (Ib) or (Ib′) into the compound (Id) or(Id′) can be effected under similar conditions as the conversion fromthe compound (IV) into the compound (X) shown above under Process (a) ofProcess 4.

Process 5:

Among the pyrroloazepine compounds (I), the compounds (Ie) and (Ie′) andthe compounds (Ih) and (Ih′) in each of which Z₁ represents a hydrogenatom and Z₂ represents a hydroxyl group can each be synthesized by anyone of the following processes.

Process (a)

Each compound (Ih) or (Ih′) is obtained in accordance with the followingreaction scheme, namely, by reducing a compound represented by theformula (IV) or (IV′) and then causing a nitrogen-containing compound(V) to act.

wherein A, R, X and Y have the same meanings as defined above.

The conversion from the compound (IV) or (IV′) into the compound (XI) or(XI′) is conducted by treating the compound (IV) or (IV′) with areducing agent such as sodium borohydride, potassium borohydride, sodiumcyanoborohydride or tri(n-butyl)tin hydride at −78° C. to refluxtemperature, preferably −20° C. to room temperature in anordinarily-employed solvent.

The conversion from the compound (XI) or (XI′) into the compound (Ih) or(Ih′) can be effected under similar conditions as the conversion fromthe compound (IV) into the compound (Ia) shown above under Process (a)of Process 2.

Process (b)

Each compound (Ie) or (Ie′) is obtained by reducing a compoundrepresented by the formula (Ib) or (Ib′) in accordance with thefollowing reaction formula.

wherein A, R and Y′ have the same meanings as defined above.

The conversion from the compound (Ib) or (Ib′) into the compound (Ie) or(Ie′) can be effected under similar conditions as in the conversion fromthe compound (IV) into the compound (XI) shown above under Process (a)of Process 5.

Process 6:

Among the pyrroloazepine compounds (I), the compounds (Ii) or (Ii′) ineach of which the bond indicated by the dashed line is present and Z₁represents a hydrogen atom can be synthesized by any one of thefollowing processes.

Process (a)

Each compound (Ii) or (Ii′) is obtained in accordance with the followingreaction scheme, namely, by subjecting a compound represented by theformula (XI) or (XI′) to a dehydrating reaction to obtain a compoundrepresented by the formula (XII) or (XII′) and then causing anitrogen-containing compound (V) to act on the compound (XII) or (XII′).

wherein A, R, X and Y have the same meanings as defined above.

In the above-described reaction, the conversion from the compound (XI)or (XI′) into the compound (XII) or (XII′) can be effected by treatingthe compound (XI) or (XI′) with an acid such as hydrogen chloride,hydrogen bromide, sulfuric acid, methanesulfonic acid orp-toluenesulfonic acid at −20° C. to 100° C., preferably at −20° C. toroom temperature in a solvent such as water, methanol, ethanol, ethylacetate, chloroform or toluene.

As an alternative, the conversion into the compound (XII) or (XII′) canalso be effected by causing methanesulfonyl chloride, p-toluenesulfonylchloride, phosphorus trichloride, phosphorus oxychloride, thionylchloride or the like and a base such as triethylamine, pyridine orcollidine to act on the compound (XI) or (XI′) in a solvent such asdichloromethane, chloroform or toluene.

The conversion from the compound (XII) or (XII′) into the compound (Ii)or (Ii′) can be effected under similar conditions as in the conversionfrom the compound (IV) into the compound (Ia) described above underProcess (a) of Process 2.

Process (b)

Each compound (Ii) or (Ii′) is also obtained by subjecting a compoundrepresented by the formula (Ih) or (Ih′) to a dehydrating reaction inaccordance with the following reaction formula:

wherein A, R and Y have the same meanings as defined above.

In the above-described reaction, the conversion from the compound (Ih)or (Ih′) into the compound (Ii) or (Ii′) can be effected under similarconditions as in the conversion from the compound (XI) into the compound(XII) described above under Process (a) of Process 6.

Process 7:

Among the pyrroloazepine compounds (I), compounds (Ij) or (Ij′) in eachof which Z₁ and Z₂ both represent hydrogen atoms can be obtained inaccordance with the following reaction scheme, namely, by reducing acompound represented by the formula (XII) or (XII′) to obtain a compoundrepresented by the formula (XIII) or (XIII′) and then reacting anitrogen-containing compound (V) to the compound (XIII) or (XIII′).

wherein A, R, X and Y have the same meanings as defined above.

In the above-described reaction, the conversion from the compound (XII)or (XII′) into the compound (XIII) or (XIII′) can be conducted bytreating, in the presence of a catalyst such as palladium-carbon orplatinum, the compound (XII) or (XII′) with hydrogen gas in anordinarily-employed solvent at −78° C. to reflux temperature, preferablyat room temperature. Further, the conversion from the compound (XIII) or(XIII′) into the compound (Ij) or (Ij′) can be effected under similarconditions as in the conversion from the compound (IV) into the compound(Ia) described above under Process (a) of Process 2.

If necessary, the compounds (I) of the present invention obtainedaccording to the above-described processes can each be reacted with oneof various acids to convert the compound into its salt. Then, theresulting salt can be purified by a method such as recrystallization orcolumn chromatography.

Exemplary acids usable for the conversion of the pyrroloazepinecompounds (I) into their salts can include inorganic acids such ashydrochloric acid, nitric acid, sulfuric acid, phosphoric acid andhydrobromic acid; and organic acids such as maleic acid, fumaric acid,tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonicacid, p-toluenesulfonic acid, adipic acid, palmitic acid and tannicacid.

Further, the compounds (I) according to the present invention includemany compounds containing asymmetric centers. Each racemic mixture canbe resolved by one or more of various methods, whereby a singleenantiomer can be obtained.

Usable methods include, for example:

(1) Resolution by an optical resolution column.

(2) Resolution by recrystallization subsequent to conversion into a saltwith a chiral acid.

(3) Resolution by an enzyme reaction.

(4) Resolution by a combination of the above methods (1) to (3).

The pyrroloazepine compounds (I) and their salts, which are obtained asdescribed above, have strong serotonin-2 blocking action and also α₁blocking action as will be demonstrated in tests to be describedsubsequently herein. From the results of a toxicity test, they have alsobeen found to possess high safety. The compounds according to thepresent invention can therefore be used as pharmaceuticals for thetreatment of circulatory diseases such as ischemic heart diseases,cerebrovascular disturbances, peripheral circulatory disturbances andhypertension.

When the pyrroloazepine compounds (I) according to this invention areused as pharmaceuticals, they can be administered in effective doses asthey are. As an alternative, they can also be formulated into variouspreparation forms by known methods and then administered.

Exemplary preparation forms as pharmaceuticals include orallyadministrable preparation forms such as tablets, capsules and syrups aswell as parenterally administrable preparation forms such as injectionsand suppositories. Whichever preparation form is used, a known liquid orsolid extender or carrier usable for the formulation of the preparationform can be employed.

Examples of such extender or carrier include polyvinylpyrrolidone,arabic gum, gelatin, sorbit, cyclodextrin, tragacanth gum, magnesiumstearate, talc, polyethylene glycol, polyvinyl alcohol, silica, lactose,crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil,carboxymethylcellulose, sodium laurylsulfate, water, ethanol, glycerin,mannitol, syrup, and the like.

When the compounds (I) according to the present invention are used aspharmaceuticals, their dose varies depending on the administrationpurpose, the age, body weight, conditions, etc. of the patient to beadministered. In oral administration, the daily dose may generally beabout 0.01-1,000 mg.

The present invention will next be described in further detail by thefollowing examples and tests. It is however to be noted that the presentinvention is by no means limited to the following examples and tests.

EXAMPLE 1

Synthesis of benzyl 3-(3-pyrrolecarboxamido)propionate (Compound No. 1)

Into a solution of 1.67 g (15 mmol) of 3-pyrrole-carboxylic acid and6.33 g (18 mmol) of β-alanine benzyl ester p-toluenesulfonate in 20 mlof dimethylformamide, a solution of 2.94 g (18 mmol) of diethylphosphorocyanidate in 10 ml of dimethylformamide was added dropwiseunder ice cooling and stirring. A solution of 3.64 g (36 mmol) oftriethylamine in 20 ml of dimethylformamide was then added dropwise. Thereaction mixture was stirred at 0° C. for 1 hour and then at roomtemperature for 24 hours.

The reaction mixture was concentrated under reduced pressure, followedby the addition of a 3:1 mixed solvent of ethyl acetate and benzene tothe residue. The resultant solution was washed successively with ahalf-saturated aqueous solution of potassium carbonate, water, a 10%aqueous solution of citric acid, water and a saturated aqueous solutionof sodium chloride. The solution was dried over anhydrous sodium sulfateand was then concentrated under reduced pressure. The residue waspurified by chromatography on a silica gel column (“Merck No. 9385” wasused as its silica gel; the same silica gel was employed in thesubsequent examples unless otherwise specifically indicated) (eluent:ethyl acetate/hexane =2:1), whereby 3.62 g of the title compound wereobtained (yield: 89%).

EXAMPLE 2

Synthesis of ethyl N-methyl-3-(3-pyrrole-carboxamido)propionate(Compound No. 2)

Into a suspension of 3.30 g (30 mmol) of 3-pyrrolecarboxylic acid in 10me of dichloromethane, a solution of 5.90 g (45 mmol) of ethylN-methyl-3-aminopropionate in 50 ml of dichloromethane, a solution of4.55 g (45 mmol) of triethylamine in 50 ml of dichloromethane, and 8.63g (45 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride were successively added, followed by stirring at roomtemperature for 3 hours. Dichloromethane was added to the reactionmixture, and the resulting organic layer was washed successively with a10% aqueous solution of citric acid, a saturated aqueous solution ofsodium hydrogencarbonate and a saturated aqueous solution of sodiumchloride. The organic layer was dried over anhydrous magnesium sulfateand was then concentrated under reduced pressure, whereby 5.31 g of thetitle compound were obtained (yield: 79%).

EXAMPLE 3

Synthesis of 3-(3-pyrrolecarboxamido)propionic acid (Compound No. 3)

Into a solution of 8.29 g (30.4 mmol) of Compound No. 1 in 200 ml oftetrahydrofuran, 829 mg of 5%-palladium-carbon were added, followed bystirring for 63 hours under a hydrogen gas stream. The reaction mixturewas filtered and the thus-obtained solid matter was washed withmethanol. The filtrate and the washing were combined and concentratedunder reduced pressure. The residue was recrystallized frommethanoldiisopropyl ether, whereby 3.89 g of the title compound wereobtained (yield: 70%).

EXAMPLE 4

Synthesis of N-methyl-3-(3-pyrrolecarboxamido)propionic acid (CompoundNo. 4)

A 2 N aqueous solution of sodium hydroxide (58 ml, 116 mmol) was addedto 5.16 g (23 mmol) of Compound No. 2, followed by stirring at roomtemperature for 1.5 hours. After the reaction mixture was washed twicewith ethyl ether, 6 N hydrochloric acid was added under ice cooling toadjust the pH of the mixture to 2. The mixture was saturated with sodiumchloride. The resultant mixture was extracted four times with ethylacetate. The extracts were combined, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The thus-obtainedcrude crystals were recrystallized from ethyl acetatehexane, whereby4.10 g of the title compound were obtained (yield: 91%).

EXAMPLE 5

Synthesis of 1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione(Compound No. 5) and2,4,5,6,7,8-hexahydropyrrolo[3,4-c]azepine-4,8-dione (Compound No. 6)

A mixture of 310 mg (1.7 mmol) of Compound No. 3 and 15.5 g ofpolyphosphoric acid (80%) was stirred for 1 hour in an oil bath of 100°C. The reaction mixture was poured into 100 g of ice water, to which a 4N aqueous solution of sodium hydroxide was added to adjust its pH to 6.The mixture was saturated with sodium chloride, followed by extraction(4 times) with tetrahydrofuran. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theresidue was fractionated and purified by chromatography on a silica gel(eluent: methanol/ chloroform=1/19→1/9), whereby 166 mg of Compound No.5 and 73 mg of Compound No. 6 were obtained (yields: 59% and 26%).

EXAMPLE 6

Synthesis of5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione (CompoundNo. 7) and 5-methyl-2,4,5,6,7,8-hexahydropyrrolo[3,4-c]azepine-4,8-dione(Compound No. 8)

A mixture of 981 mg (5 mmol) of Compound No. 4 and 50 g ofpolyphosphoric acid (80%) was stirred for 30 minutes in an oil bath of100° C. The reaction mixture was poured into 200 g of ice water, towhich a 4 N aqueous solution of sodium hydroxide was added to adjust itspH to 5. The mixture was saturated with sodium chloride, followed byextraction (thrice) with tetrahydrofuran. The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The residue was fractionated and purified by chromatography on a silicagel (eluent: methanol/chloroform=3/97), whereby 653 mg of Compound No. 7and 178 mg of Compound No. 8 were obtained (yields: 73% and 20%).

EXAMPLE 7

Synthesis of1-(4-chlorobutyl)-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione(Compound No. 9)

A suspension of 3.03 g (17 mmol) of Compound No. 7, 9.40 g (68 mmol) ofpotassium carbonate and 11.66 g (68 mmol) of 1-bromo-4-chlorobutane in100 ml of 2-butanone was refluxed for 11 hours. The reaction mixture wasfiltered, and the thus-obtained solid matter was washed with 2-butanone.The filtrate and the washing were combined and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column (eluent: methanol/chloroform=1/99), whereby 4.46 g of thetitle compound were obtained (yield: 98%).

EXAMPLE 8

Synthesis of1-(4-bromobutyl)-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione(Compound No. 10)

A suspension of 178 mg (1 mmol) of Compound No. 7, 691 mg (5 mmol) ofpotassium carbonate and 0.6 ml (5 mmol) of 1,4-dibromobutane in 20 ml ofdimethyl-formamide was stirred for 1 hour in an oil bath of 80° C. Thereaction mixture was concentrated under reduced pressure. Ice water wasadded to the residue, followed by neutralization with 6 N hydrochloricacid. The thus-obtained mixture was extracted with chloroform (thrice).The organic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column (eluent: ethyl acetate), whereby 254 mg of the title compoundwere obtained (yield: 81%).

EXAMPLE 9

Synthesis of2-(4-chlorobutyl)-5-methyl-2,4,5,6,7,8-hexahydropyrrolo[3,4-c]azepine-4,8-dione(Compound No. 11)

A suspension of 891 mg (5 mmol) of Compound No. 8, 2.76 g (20 mmol) ofpotassium carbonate and 3.43 g (20 mmol) of 1-bromo-4-chlorobutane in 40ml of 2-butanone was refluxed for 11 hours. The reaction mixture waspost-treated in a similar manner as in Example 7 and the residue waspurified by chromatography on a silica gel column (eluent:methanol/chloroform=1/49), whereby 1.29 g of the title compound wereobtained (yield: 96%).

EXAMPLE 10

Synthesis of1-(4-chlorobutyl)-8-hydroxyimino-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one(Compound No. 12)

A solution of 134 mg (0.5 mmol) of Compound No. 9 and 42 mg (0.6 mmol)of hydroxylamine hydrochloride in 10 ml of methanol was refluxed for 190hours. The reaction mixture was concentrated under reduced pressure. Ahalf-saturated aqueous solution of potassium carbonate was added to theresidue, followed by extraction (twice) with chloroform. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (eluent: methanol/chloroform=1/99→1/49), whereby 70 mg of thetitle compound were obtained (yield: 49%).

EXAMPLE 11

Synthesis of2-(4-chlorobutyl)-8-hydroxyimino-5-methyl-2,4,5,6,7,8-hexahydropyrrolo[3,4-c]azepin-4-one(Compound No. 13)

A solution of 537 mg (2 mmol) of Compound No. 11, 278 mg (4 mmol) ofhydroxylamine hydrochloride and 328 mg (4 mmol) of sodium acetate in 20ml of methanol was refluxed for 4 hours. The reaction mixture waspost-treated in a similar manner as in Example 10 and the residue waspurified by chromatography on a silica gel column (eluent: ethylacetate), whereby 273 mg of the title compound were obtained (yield:48%).

EXAMPLE 12

Synthesis of 1-(4-chlorobutyl)-8-hydroxy-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one (Compound No. 14)

Into a solution of 269 mg (1 mmol) of Compound No. 9 in 15 ml ofethanol, 378 mg (10 mmol) of sodium borohydride were added under icecooling and stirring, followed by stirring at room temperature for 18hours. Water (15 ml) was added to the reaction mixture. The resultantmixture was stirred at room temperature for 2 hours and thenconcentrated under reduced pressure. Water was added to the residue,followed by extraction (twice) with ethyl acetate. The organic layer waswashed with a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The residue was purified by chromatography on a silica gel column(eluent: methanol/chloroform=1/49), whereby 246 mg of the title compoundwere obtained (yield: 91%).

EXAMPLE 13

Synthesis of1-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione(Compound No. 15)

A suspension of 100 mg (0.32 mmol) of Compound No. 10, 364 mg (0.96mmol) of 4-(4-fluorobenzoyl)piperidine p-toluenesulfonate, 265 mg (1.92mmol) of potassium carbonate and 54 mg (0.38 mmol) of sodium iodide in20 ml of dimethylformamide was stirred for hours in an oil bath of 80°C. Water was added to the reaction mixture, followed by extraction witha 3:1 mixed solvent of ethyl acetate and benzene. The organic layer waswashed with water (twice) and a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure. The residue was purified by chromatography on asilica gel column (eluent: methanol/chloroform=1/19), whereby 123 mg ofthe title compound were obtained (yield: 88%).

EXAMPLE 14

Synthesis of5-methyl-1-[4-(4-phenylpiperazin-1-yl)butyl]-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione(Compound No. 16)

A suspension of 269 mg (1 mmol) of Compound No. 9, 162 mg (1 mmol) ofN-phenylpiperazine, 168 mg (2 mmol) of sodium hydrogencarbonate and 300mg (2 mmol) of sodium iodide in 15 ml of acetonitrile was refluxed for11 hours. The reaction mixture was post-treated in a similar manner asin Example 10 and the residue was purified by chromatography on a silicagel column (eluent: methanol/chloroform=1/49), whereby 360 mg of thetitle compound were obtained (yield: 91%).

EXAMPLE 15

Synthesis of1-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]butyl]-5-methyl-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-4,8-dione(Compound No. 17)

A suspension of 269 mg (1 mmol) of Compound No. 9, 220 mg (1 mmol) of4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine, 168 mg (2 mmol) of sodiumhydrogencarbonate and 300 mg (2 mmol) of sodium iodide in 15 ml ofacetonitrile was refluxed for 20 hours. The reaction mixture waspost-treated in a similar manner as in Example 10. The residue waspurified by chromatography on a silica gel column (eluent:methanol/chloroform=3/97), whereby 406 mg of the title compound wereobtained (yield: 90%).

EXAMPLE 16

Synthesis of2-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-5-methyl-2,4,5,6,7,8-hexahydropyrrolo[3,4-c]azepine-4,8-dione(Compound No. 18)

A suspension of 134 mg (0.5 mmol) of Compound No. 11, 122 mg (0.5 mmol)of 4-(4-fluorobenzoyl)piperidine hydrochloride, 168 mg (2 mmol) ofsodium hydrogencarbonate and 150 mg (1 mmol) of sodium iodide in 10 mlof acetonitrile was refluxed for 25 hours. The reaction mixture waspost-treated in a similar manner as in Example 10 and the residue waspurified by chromatography on a silica gel column (eluent:methanol/chloroform=3/97), whereby 186 mg of the title compound wereobtained (yield: 85%).

EXAMPLE 17

Synthesis of1-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-8-hydroxyimino-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one(Compound No. 19)

A suspension of 57 mg (0.2 mmol) of Compound NO. 12, 54 mg (0.22 mmol)of 4-(4-fluorobenzoyl)piperidine hydrochloride, 74 mg (0.88 mmol) ofsodium hydrogencarbonate and 66 mg (0.44 mmol) of sodium iodide in 10 mlof acetonitrile was refluxed for 40 hours. The reaction mixture waspost-treated in a similar manner as in Example 10 and the residue waspurified by chromatography on a silica gel column (eluent:methanol/chloroform=3/97→1/19), whereby 72 mg of the title compound wereobtained (yield: 79%).

EXAMPLE 18

Synthesis of8-hydroxyimino-5-methyl-l-[4-(4-phenylpiperazin-1-yl)butyl]-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-4-one(Compound No. 20)

A solution of 70.4 mg (0.18 mmol) of Compound No. 16 and 29 mg (0.4mmol) of hydroxylamine hydrochloride in 5 ml of pyridine was stirred for77 hours in an oil bath of 70° C. The reaction mixture was post-treatedin a similar manner as in Example 10 and the residue was purified bychromatography on a silica gel column (eluent:methanol/chloroform=3/97), whereby 47 mg of the title compound wereobtained (yield: 64%).

EXAMPLE 19

Synthesis of2-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-8-hydroxyimino-5-methyl-2,4,5,6,7,8-hexahydropyrrolo[3,4-c]azepin-4-one(Compound No. 21)

A suspension of 142 mg (0.5 mmol) of Compound No. 13, 122 mg (0.5 mmol)of 4-(4-fluorobenzoyl)piperidine hydrochloride, 168 mg (2 mmol) ofsodium hydrogencarbonate and 150 mg (1 mmol) of sodium iodide in 10 mlof acetonitrile was refluxed for 22 hours. The reaction mixture waspost-treated in a similar manner as in Example 10 and the residue waspurified by chromatography on a silica gel column (eluent:methanol/chloroform=1/9), whereby 202 mg of the title compound wereobtained (yield: 89%).

EXAMPLE 20

Synthesis of1-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-8-hydroxy-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one(Compound No. 22)

A suspension of 217 mg (0.8 mmol) of Compound No. 14, 214 mg (0.88 mmol)of 4-(4-fluorobenzoyl)piperidine hydrochloride, 296 mg (3.52 mmol) ofsodium hydrogencarbonate and 264 mg (1.76 mmol) of sodium iodide in 15ml of acetonitrile was refluxed for 24 hours. The reaction mixture waspost-treated in a similar manner as in Example 10 and the residue waspurified by chromatography on a silica gel column (eluent:methanol/chloroform=1/19→2/23), whereby 295 mg of the title compoundwere obtained (yield: 84%).

In the same manner or a similar manner as in any of the Examplesdescribed above, the following compounds are obtained.

(1)1-[3-[4-(4-Fluorobenzoyl)piperidino]propyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(2)1-[5-[4-(4-Fluorobenzoyl)piperidino]pentyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(3)2-[3-[4-(4-Fluorobenzoyl)piperidino]propyl]-5-methyl-2,4,5,6,7,8-hexahydropyrrolo[3,4-c]azepine-4,8-dione

(4)2-[5-[4-(4-Fluorobenzoyl)piperidino]pentyl]-5-methyl-2,4,5,6,7,8-hexahydropyrrolo[3,4-c]azepine-4,8-dione

(5)1-[4-[4-(4-Fluorobenzoyl)piperidino]butyl]-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(6)5-Ethyl-1-[4-[4-(4-fluorobenzoyl)piperidino]butyl]-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(7)1-[4-[4-(4-Fluorobenzoyl)piperidino]butyl]-5-propyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(8)1-[4-[4-(4-Fluorobenzoyl)piperidino]butyl]-5-isopropyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(9)5-Butyl-1-[4-[4-(4-fluorobenzoyl)piperidino]butyl]-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(10)5-Benzyl-1-[4-[4-(4-fluorobenzoyl)piperidino]butyl]-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(11)1-[4-[4-(4-Fluorobenzoyl)piperidino]butyl]-5-methyl-1,4,5,6-tetrahydropyrrolo[3,2-c]azepin-4-one

(12)1-[4-[4-(4-Fluorobenzoyl)piperidino]butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one

(13)8,8-Bis(ethylthio)-1-[4-[4-(4-fluorobenzoyl)piperidino]butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one

(14)1-[4-[4-(4-Fluorobenzoyl)piperidino]butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one-8-spiro-2′-(1′,3′-dithiolane)

(15)1-[4-[4-(2-Furoyl)piperazin-1-yl]butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(16)1-[4-[4-(Bis(4-fluorophenyl)methylene]piperidino]butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(17)1-[4-[4-(6-Fluoro-1H-indazol-3-yl)piperidino]butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(18)1-[4-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)piperidino]butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(19)1-[4-[4-(4-Chlorobenzoyl)piperidino]butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(20)1-[4-[4-(4-Fluorophenoxy)piperidino]butyl]-5-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(21)1-[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]butyl]-1,4,5,6,7,8-hexahydropyrrolo-[3,2-c]azepine-4,8-dione

(22)5-Ethyl-1-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]butyl]-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(23)1-[4-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)piperidino]butyl]-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione

(24)5-Ethyl-1-[4-[4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidino]butyl]-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-4,8-dione

(25)2-[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]butyl]-5-methyl-2,4,5,6,7,8-hexahydropyrrolo[3,4-c]azepine-4,8-dione

Physical data of the compounds obtained above in Examples 1-20 are shownin Tables 1-6.

TABLE 1 Property Melting point Comp'd Structural (recrystalli- NMR (δppm)* IR (cm⁻¹) No. formula zation solvent) ( ): observation frequency (): measuring method 1

Brown oil (270 MHz) 2.64 (2H, t, J = 5.9 Hz), 3.65 (2H, m), 5.11 (2H,s), 6.33 (1H, m), 6.59 (1H, m), 6.68 (1H, m), 7.22 (1H, m), 7.29-7.31(5H, m), 9.90 (1H, br.s) (film) 3271, 2954, 1732, 1634, 1567, 1520,1338, 1254, 1210, 1172, 756, 698 2

Brown oil (400 MHz) 1.26 (3H, t, J = 7.1 Hz), 2.67 (2H, t, J = 7.1 Hz),3.18 (3H, s), 3.81 (2H, t, J = 7.1 Hz), 4.15 (2H, q, J = 7.1 Hz), 6.44(1H, m), 6.74 (1H, m), 7.18 (1H, m), 8.73 (1H, br.s) (film) 3232, 2980,1731, 1594, 1546, 1508, 1438, 1401, 1375, 1314, 1190, 1106, 1046, 968,756 3

Colorless needle crystals 178.5-183.0° C. (methanol- isopropyl ether)(400 MHz) (DMSO-de/TMS) 2.45 (2H, t, J = 7.1 Hz), 3.36 (2H, m), 6.43(1H, s), 6.71 (1H, s), 7.26 (1H, s), 7.72 (1H, m), 11.04 (1H, br.s),12,09 (1H, s) (KBr) 3381, 3272, 1718, 1567, 1538, 1427, 1351, 1210, 853,757 4

Pale yellow powdery crystals 125.0-127.5° C. (ethyl acetate- hexane)(400 MHz) (DMSO-de/TMS) 2.52 (2H, m), 3.05 (3H, s), 3.63 (2H, t, J = 7.3Hz), 6.29 (1H, m), 6.74 (1H, m), 7.12 (1H, m), 11.11 (1H, br.s), 12.24(1H, br.s) (KBr) 3330, 3122, 1721, 1574, 1516, 1407, 1305, 1211, 1098,906, 752 *Measured in COCl₃ with TMS as an internal standard unlessotherwise specifically indicated.

TABLE 2 Property Melting point Comp'd Structural (recrystalli- NMR (δppm)* IR (cm⁻¹) No. formula zation solvent) ( ): observation frequency (): measuring method 5

Colorless needle crystals 285-287° C. (decomp'd) (methanol- isopropylether) (400 MHz) (DMSO-d₆/TMS) 2.71(2H, m), 3.33(2H, m), 6.57 (1H, s),7.11(1H, d, J=2.4Hz), 8.29(1H, m), 12.13(1H, br. s) (KBr) 3306, 3037,2956, 1642, 1503, 1438, 1407, 1395, 1268, 882, 762 6

Colorless powdery crystals 287° C. min. (methanol- isopropyl ether) (400MHz) (DMSO-d₆/TMS) 2.65(2H, m), 3.29(2H, m), 7.34 (1H, s), 7.43(1H, s),7.80 (1H, m), 11.97(1H, br. s) (KBr) 3309, 3120, 3057, 2946, 2880, 1647,1620, 1526, 1474, 1456, 1419, 1377, 1360, 910, 838, 810, 759 7

Colorless prism crystals 224.0-225.5° C. (chloroform-hexane) (400 MHz)2.86(2H, m), 3.23(3H, s), 3.71 (2h, m), 6.89(1H, t, J=2.8Hz), 7.04(1H,t, J=2.8Hz), 9.41 (1H, br. s) (KBr) 3186, 1664, 1611, 1548, 1500, 1401,1365, 1277, 1232, 1188, 1112, 1090, 955, 927, 890, 827, 785, 761, 692 8

Colorless prism crystals 175.0-176.5° C. (chloroform-hexane) (400 MHz)2.84(2H, m), 3.21(3H, s), 3.68 (2H, m), 7.41(1H, m), 7.47(1H, m),10.32(1H, br. s) (KBr) 3108, 2956, 1622, 1522, 1490, 1451, 1391, 1243,1171, 1098, 958, 924, 863, 815, 758 *Measured in CDCl₃ with TMS as aninternal standard unless otherwise specifically indicated.

TABLE 3 Property Melting point Structural (recrystalli- NMR (δ ppm)* IR(cm⁻¹) Comp'd No. formula zation solvent) ( ): observation frequency (): measuring method 9

Colorless needle crystals 88.0-89.0° C. (ethanol- isopropyl ether) (270MHz) 1.80(2H, s), 1.91(2H, m), 2.85(2H, m), 3.22(3H, s), 3.53(2H, t,J=6.6Hz), 3.66(2H, m), 4.35)2H, t, J=6.6Hz), 6.79(1H, d, J=2.6Hz),6.89(1H, d, J=2.6Hz) (KBr) 2937, 1630, 1522, 1504, 1410, 1318, 1246,1178, 1095, 912, 862, 798, 750, 724 10

Colorless needle crystals 92.0-93.0° C. (ethyl acetate- hexane) (270MHz) 1.80-1.99(4H, m), 2.85(2H, m), 3.22(3H, s), 3.39(2H, t, J=5.9Hz),3.66(2H, m), 4.34(2H, t, J=6.6Hz) 6.79(1H, d, J=2.6Hz), 6.89 (1H, d,J=2.6Hz) (KBr) 3630, 2934, 1649, 1630, 1505, 1410, 1247, 1180, 1098,911, 752 11

Colorless powdery crystals 112.0-113.5° C. (chloroform-ether) (400 MHz)1.77(2H, m), 1.99(2H, m), 2.81(2H, m), 3.19(3H, s), 3.54(2H, t,J=6.3Hz), 3.66(2H, m), 3.96(2H, t, J=7.0Hz), 7.33(2H, m) (KBr) 3116,2948, 1655, 1624, 1540, 1519, 1490, 1406, 1318, 1244, 1169, 925, 879,761 12

Colorless prism crystals 194.0-195.5° C. (ethyl acetate- hexane) (400MHz)(DMSO-d₆/TMS) 1.63(2H, m), 1.78(2H, m), 2.89 (2H, m), 2.97(3H, s),3.42(2H, m), 3.58(2H, t, J=6.6Hz), 4.19 (2H, t, J=6.9Hz), 6.36(1H, d, J=2.9Hz), 6.94(1H, d, J=2.9Hz) (KBr) 3154, 2937, 1591, 1508, 1397, 1322,1250, 1203, 1099, 1028, 972, 934 916, 776, 741, 684 *Measured in CDCl₃with TMS as an internal standard unless otherwise specificallyindicated.

TABLE 4 Property Melting point IR (cm⁻¹) Comp'd Structural (recrystalli-NMR (δ ppm)* ( ): measuring No. formula zation solvent) ( ): observationfrequency method 13

Colorless prism crystals 184.0-186.0° C. (methanol) (400MHz)(DMSO-d₆/TMS) 1.66(2H, m), 1.84(2H, m), 2.78 (2H, m), 2.96(3H, s),3.42(2H, m), 3.63(2H, t, J=6.6Hz), 3.96(2H, t, J= 6.9Hz), 7.02(1H, d,J=2.5Hz), 7.27(1H, d, J=2.5Hz), 10.64(1H, s) (KBr) 3230, 1598, 1530,1408, 1360, 1325, 1247, 1186, 1144, 1044, 968, 950, 917, 826, 794, 67914

Colorless prism crystals 106.5-111.5° C. (ethyl acetate- hexane) (400MHz) 1.82(2H, m), 1.98(2H, m), 2.23 (2H, m), 3.09(3H, s), 3.29(1H, m),3.54(2H, dt, J=1.7Hz, 6.3Hz), 3.64(1H, m), 3.97(1H, m), 4.15 (1H, m),4.91(1H, m), 6.66 (1H, d, J=2.9Hz) 6.72(1H, d, J= 2.9Hz) (KBr) 3251,2930, 2871, 1593, 1545, 1512, 1466, 1390, 1316, 1292, 1258, 1211, 1102,1057, 962, 722 15

(270 MHz) 1.62(2H, m), 1.79(2H, m), 1.75-2.45 (6H, m), 2.50(2H, m),2.84(2H, m), 3.00(2H, m), 3.22(3H, s), 3.29(1H, m), 3.66(2H, m),4.33(2H, m), 6.78(1H, d, J= 2.6Hz), 6.91(1H, d, J=2.6Hz), 7.14 (2H, t,J=8.6Hz), 7.95(2H, dd, J= 5.3Hz, 8.6Hz), (CHCl₃) 2940, 2800, 1680, 1650,1620, 1600, 1500, 1410, 1390, 1050, 975, 910 16

Pale yellow prism crystals 93.0-95.0° C. (ethyl acetate- hexane) (400MHz) 1.55(2H, m), 1.80(2H, m), 2.40(2H, m), 2.58(4H, m), 2.84(2H, m),3.19(4H, m), 3.21(3H, s), 3.65(2H, m), 4.34(2H, t, J= 7.2Hz), 6.78(1H,d, J=2.6Hz), 6.85 (1H, m), 6.88-6.95(3H, m), 7.26(2H, m) (KBr) 3089,2811, 1634, 1499, 1407, 1384, 1309, 1227, 1138, 926, 804, 758, 695*Measured in CDCl₃ with TMS as an internal standard unless otherwisespecifically indicated.

TABLE 5 Property Melting point IR (cm⁻¹) Comp'd Structural (recrystalli-NMR (δ ppm)* ( ): measuring No. formula zation solvent) ( ): observationfrequency method 17

Pale yellow powdery crystals 114.0-117.0° C. (2-propanol) (400 MHz)1.55(2H, m), 1.80(2H, m), 2.00-2.17 (6H, m), 2.40(2H, m), 2.85(2H, m),2.98-3.12(3H, m), 3.22(3H, s), 3.65 (2H, m), 4.34(2H, t, J=7.2Hz),6.79(1H, d, J=2.6Hz), 6.91(1H, d, J=2.6Hz), 7.05(1H, d, t, J= 2.1Hz,8.9Hz), 7.23(1H, dd, J= 2.1Hz, 8.5Hz), 7.69(1H, dd, J= 5.1Hz, 8.7Hz) #(KBr) 3098, 2944, 1652, 1616, 1502, 1395, 1316, 1269, 1250, 1137, 960,905, 830, 758 18

Colorless powdery crystals (173.5-175.5° C. (ethanol- ether) (400 MHz)1.49(2H, m), 1.75-1.90(6H, m), 2.07(2H, m), 2.35(2H, m), 2.80(2H, m),2.93(2H, m), 3.14-3.22(4H, m), 3.65(2H, m), 3.93(2H, t, J= 7.1Hz),7.13(2H, m), 7.33(2H, m), 7.95(2H, m) (KBr) 3120, 2945, 1670, 1608,1541, 1519, 1445, 1394, 1323, 1248, 1210, 1177, 1144, 972, 860, 762 19

Colorless oil (400 MHz) 1.54(2H, m), 1.77(2H, m), 1.82-1.90 (4H, m),2.14(2H, m), 2.39(2H, t, J=7.4Hz), 2.97(2H, m), 3.02(2H, m), 3.12(3H,s), 3.22(1H, quint, J= 7.3Hz), 3.50(2H, m), 4.16(2H, t, J=7.2Hz),6.65(1H, d, J= 2.8Hz), 6.69(1H, d, J=2.8Hz), 7.13(2H, m), 7.95(2H, m)(KBr) 2945, 1680, 1598, 1505, 1397, 1244, 1209, 1158, 974, 937, 854, 73620

Colorless prism crystals 200.0-203.0° C. (methanol- chloroform) (270MHz) 1.55(2H, m), 1.74(2H, m), 2.43 (2H, m), 2.64(4H, m), 2.98(2H, m),3.10(3H, s), 3.22(4H, m), 3.48(2H, m), 4.14(2H, m), 6.64(1H, d, J=2.6Hz), 6.67(1H, d, J=2.6Hz), 6.82-6.96(3H, m), 7.26(2H, m), 10.95(1H, br.s) (CHCl₃) 3570, 2940, 2825, 1620, 1600, 1500, 1395, 1090, 970, 910*Measured in CDCl₃ with TMS as an internal standard unless otherwisespecifically indicated.

TABLE 6 Property Melting point IR (cm⁻¹) Comp'd Structural (recrystalli-NMR (δ ppm)* ( ): measuring No. formula zation solvent) ( ): observationfrequency method 21

Colorless powdery crystals 172.0-178.0° C. (chloroform) (400 MHz)1.51(2H, m), 1.75-1.90(6H, m), 2.07(2H, m), 2.36(2H, m), 2.90- 3.00(4H,m), 3.11(3H, s), 3.18(1H, m), 3.53(2H, m), 3.89(2H, t, J= 7.1Hz),6.95(1H, d, J=2.5Hz), 7.13(2H, m), 7.27(1H, d, J=2.5Hz), 7.84(1H, br.s), 7.95(2H, m) (KBr) 2942, 1677, 1598, 1537, 1508, 1410, 1324, 1215,1142, 1039, 969, 913, 856, 796 22

Colorless prism crystals 173.0-175.5° C. (chloroform- ether) (400 MHz)1.59(2H, m), 1.74-2.07(8H, m), 2.12- 2.36(4H, m), 2.82(1H, m), 2.95(1H,m), 3.13(3H, s), 3.18(1H, m), 3.30(1H, m), 3.75(1H, m), 4.01(2H, t,J=7.4Hz), 4.92(1H, t, J=4.4Hz), 6.63(1H, d, J=2.9Hz), 6.74(1H, d,J=2.9Hz), 7.13(2H, m), 7.94(2H, m), (KBr) 3274, 2935, 2808, 1672, 1586,1511, 1317, 1284, 1207, 1154, 1101, 1057, 973, 856, 740 *Measured inCDCl₃ with TMS as an internal standard unless otherwise specificallyindicated.

Tests

With respect to the compounds of the present invention, their anti-α₁action and anti-serotonin (5-HT) action were investigated by the methodswhich will be described below. The results of some representativecompounds are shown in Table 7.

(1) Anti-α₁ action

The thoracic aorta of each Hartley male guinea pig (body weight: 300-500g) was excised. A preparation cut in a helical form was suspended under1 g load in a Magnus cylinder filled with the Tyrode solution which hadbeen aerated with a gas mixture of 95% O₂ and 5% CO₂ and maintained at37° C. Using an isometric transducer (“TB-612J”, manufactured by NihonKohden Corporation) and a pressure preamplifier (“AP-620G”, manufacturedby Nihon Kohden Corporation), variations in tension were measured. Theisometric tensions were recorded on a thermal pen-writing recorder(“WT-647G”, manufactured by Nihon Kohden Corporation). Taking the toniccontraction induced by 10⁻⁵ M norepinephrine (NE) as 100%, the percentcontractions upon addition of each test drug at 10⁻⁸ M and 10−7 M weredetermined as anti-α₁action.

(2) Anti-serotonin (5-HT) action

The superior mesenteric artery of each Hartley male guinea pig (bodyweight: 300-500 g) was excised. A preparation cut in a helical form wassuspended under resting tension of 0.3 g in a Magnus cylinder filledwith the Tyrode solution which had been aerated with a gas mixture of95% O₂ and 5% CO₂ and maintained at 37° C. Using an isometric transducer(“UL-10”, manufactured by SHINKOH K.K.) and a pressure preamplifier(“DSA-605A”, manufactured by SHINKOH K.K.), variations in tension weremeasured. The isometric tensions were recorded on a pen-writing recorder(“VP-6537A”, manufactured by NATIONAL K.K.). Taking the contractioninduced by 10⁻⁵ M serotonin (5-HT) as 100%, the percent contractions by10⁻⁵ M 5-HT in the presence of each test drug at 10⁻⁸ M, 10⁻⁷ M and 10⁻⁶M were determined as anti-5-HT action.

(3) Results

TABLE 7 Anti α₁ action Anti 5-HT action Comp'd (% of Control) (% ofControl) No. 10⁻⁸M 10⁻⁷M 10⁻⁸M 10⁻⁷M 10⁻⁶M 15 59.9 35.4 NT 75.3 26.6 1727.8 14.0 80.7 55.2  8.9 18 76.0 37.3 NT 81.7 25.3 21 69.7 36.9 NT 85.524.9

Capability of Exploitation in Industry

The pyrroloazepine derivatives (I) and their salts according to thepresent invention have strong α₁-blocking action and serotonin-2blocking action, and also have high safety. Accordingly, the presentinvention has made it possible to provide preventives or therapeuticsfor general circulatory diseases such as hypertension, heart failure,.ischemic heart diseases, cerebrovascular disturbances and peripheralcirculatory disturbances.

What is claimed is:
 1. An intermediate for the production of apharmaceutical, which is represented by the following formula (IIa) or(IIa′):

wherein R′ represents a linear or branched alkyl group, a cycloalkylgroup, a cycloalkyl-alkyl group or substituted or unsubstituted aralkylgroup.
 2. An intermediate for the production of a pharmaceutical, whichis represented by the following formula (XIV) or (XIV′):

wherein the dashed line indicates the presence or absence of a bond;and, when the bond indicated by the dashed line is present, Z₂ is notpresent and Z₁ represents a hydrogen atom but, when the bond indicatedby the dashed line is absent, Z₁ and Z₂ both represent hydrogen atoms;Z₁ represents a hydrogen atom and Z₂ represents a hydroxyl group; Z₁ andZ₂ both represent groups SR₅ in which R₅ represents a substituted orunsubstituted alkyl group, a substituted or unsubstituted aralkyl groupor a substituted or unsubstituted aryl group, wherein said group may besubstituted with one or more of halogen atoms, alkyl groups having 1-4carbon atoms and alkoxy groups having 1-4 carbon atoms; Z₁ and Z₂ arecombined together to represent an oxygen atom, a group NOR₆ in which R₆represents a hydrogen atom, a substituted or unsubstituted alkyl group,a substituted or unsubstituted aralkyl group or a substituted orunsubstituted aryl group, wherein said group may be substituted with oneor more of halogen atoms, alkyl groups having 1-4 carbon atoms andalkoxy groups having 1-4 carbon atoms, or a group represented by theformula:

in which G represents a substituted or unsubstituted ethylene group or asubstituted or unsubstituted trimethylene group, wherein said group maybe substituted with one or more of halogen atoms, alkyl groups having1-4 carbon atoms, aryl groups having 6-14 carbon atoms, aralkyl groupshaving 7-22 carbon atoms and alkylidene groups having 1-4 carbon atoms;A represents an alkylene group, an alkenylene group or an alkynylenegroup R represents a hydrogen atom, a linear or branched alkyl group, acycloalkyl group, a cycloalkyl-alkyl group or a substituted orunsubstituted aralkyl group, wherein said aralkyl group may besubstituted with one or more of halogen atoms, alkyl groups having 1-4carbon atoms and alkoxy groups having 1-4 carbon atoms; and X representsan eliminative groups.
 3. A process for the preparation of apyrroloazepine compound represented by the following formula (IIa) or(IIa′):

wherein R′ represents a linear or branched alkyl group, a cycloalkylgroup, a cycloalkyl-alkyl group or a substituted or unsubstitutedaralkyl group, which comprises: reacting a β-aminopropionic acid or aderivative thereof, which is represented by the following formula (XVI):R′NHCH₂CH₂COOR₇  (XVI) wherein R₇ represents a hydrogen atom or acarboxyl-protecting group, and R′ is as defined above, with apyrrole-3-carboxylic acid or a derivative thereof represented by thefollowing formula (XV):

wherein Q represents a hydroxyl group, an alkoxy group or an eliminativegroup easily replaceable by an amino group, to produce a compoundrepresented by the following formula (XVII):

wherein R′ is as defined above, and R₇ represents a hydrogen atom or acarbonyl protecting group, and then subjecting the compound representedby the formula (XVII) to ring closure.
 4. An intermediate for theproduction of a pharmaceutical, which is represented by the followingformula (XVII):

wherein R′ represents a linear or branched alkyl group, a cycloalkylgroup, a cycloalkyl-alkyl group or a substituted or unsubstitutedaralkyl group; and R⁷ represents a hydrogen atom or acarboxyl-protecting group.